The term “myeloid neoplasias” (MNs) encompasses several classes of disorders, among them myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDS), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), as well as related disorders.
Myeloproliferative neoplasms (MPNs), such as polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) are clonal hematopoietic disorders typified by an overproduction of terminally differentiated cells in part as a result of hypersensitivity of marrow progenitor cells to hematopoietic growth factors.
The molecular etiology of myeloproliferative neoplasms (MPNs) remains incompletely understood, despite recent advances incurred through the discovery of a point mutation in the JAK2 kinase (JAK2V617F) in a large proportion of patients. Several lines of evidence support the hypothesis that additional aberrations, either preceding or following acquisition of the JAK2V617F mutation, contribute to the pathophysiology of these disorders.
The transcription factor Nuclear factor erythroid-2 (NF-E2) is crucial for regulating erythroid-specific gene expression. Cloning of the NF-E2 p45 protein has revealed that it contains a basic region-leucine zipper (b-zip) domain which associates with proteins of the Maf family to form functional NF-E2 [Igarashi et al., Nature (1994), 367, 568-572].
Nuclear factor erythroid-2 (NF-E2), a hematopoietic transcription factor, is overexpressed in a large majority of patients with polycythemia vera (PV) (Goerttler et al. [British Journal of Hematology 129 (2005) 138-150]. NF-E2 is essential for platelet formation as knock-out mice die perinatally of hemorrhage due to thrombocytopenia. In addition, loss of NF-E2 also affects the erythroid lineage since surviving adult mice display mild anemia with compensatory reticulocytosis.
Wang et al. [Blood (2010), pp 254-266] have shown that the transcription factor NF-E2 is overexpressed not only in the majority of patients with polycythemia vera but also in patients with essential thrombocytemia (ET) and primary myelofibrosis (PMF) independent of the presence or absence of the JAK2 mutation.
Toki et al teach that the NF-E2 mRNA is transcribed from two alternative promotors called NF-E2 1A and NF-E2 1F which are located on different exons (exon 1A and exon 1F, respectively) Toki et al, 2000, Exp. Hematol. 28: 1113-1119). The exons 1A and 1F are non-coding. The translation of NF-E2 starts in exon 2 and is continued in exon 3.